Over 16 million patients are estimated to have coronary artery disease (CAD) in the United States alone. Whereas some patients will have quiescent disease, others will suffer plaque rupture and develop acute, overt ischemic complications. Thus, a major challenge for clinicians is to identify which of their patients with apparently stable CAD are, in fact, vulnerable to major adverse outcomes in the ensuing years. Until recently, cardiovascular biomarkers have been primarily limited to cardiomyocyte-derived proteins released during myocardial infarction (MI), and thus have been restricted to diagnosing a major complication of CAD after it has occurred. However, a greater understanding of the complexity of atherothrombosis has catalyzed an interest in examining novel biomarkers that may provide reliable, non-invasive biochemical detection of the underlying pathobiological processes that render patients vulnerable to future cardiovascular events, including oxidative stress, leukocyte recruitment & activation, endothelial cell dysfunction, fibrous cap degradation, and platelet activation. Moreover, candidate biomarker selection can now additionally be informed by data from omics profiling including genomics and metabolomics. Specifically, the results from several recently completed genome-wide association studies have implicated several proteins previously not thought to play a role in CAD. Similarly, recent advances in mass spectrometry based metabolic profiling technologies have enabled the monitoring of hundreds of metabolites from biological samples. These lipids, sugars, and amino acids serve as substrates and products for metabolic pathways that may be deranged very early in disease states. The combination of proteins from known, pathobiologically relevant pathways plus proteins and metabolites not previously suspected to play a role in coronary disease but identified and validated through unbiased investigative approaches offers the best chance to develop a biomarker panel that offers substantial rather than simply incremental advances in prognosis. Thus, the overall goal of this proposal is to determine the ability of novel biomarkers to predict major adverse cardiovascular outcomes in patients with chronic CAD. We will utilize a cost-efficient staged approach to assess candidate biomarkers in blood samples from 3778 patients from PEACE, an NIH-sponsored clinical trial of the angiotensin-converting enzyme (ACE) inhibitor trandolapril in patients with chronic CAD. In Aim 1 we will investigate the prognostic utility of 14 novel protein biomarkers for adverse cardiovascular outcomes in a nested case-cohort study of 1100 patients from PEACE. In Aim 2 we will use metabolomics to identify and validate the association of metabolites with adverse cardiovascular outcomes in 2 nested case-control studies. In Aim 3 we will fully characterize the prognostic utility of promising novel biomarkers in the entire trial cohort and combine traditional risk factors and multiple biomarkers to create comprehensive risk prediction tools. PUBLIC HEALTH RELEVANCE: Over 16 million patients are estimated to have coronary artery disease in the United States alone, and despite modern therapy, these patients remain at significant risk for future adverse cardiovascular outcomes such as death, recurrent heart attacks, and strokes. Our greater understanding of what causes plaques to build up in arteries and eventually rupture has created an opportunity to develop blood tests that might better predict which individuals are at high risk for disease progression; such tests might also be used by physicians to target therapy to patients who would reap the greatest benefit. Our goal is to evaluate potential new blood tests that may predict recurrent heart disease and determine which ones offer the greatest value.